Single myonuclei RNA-seq on control vs AAV-OPDM mouse models
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE314684 | GEO | 2026/02/03
REPOSITORIES: GEO
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Project description:Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by GGC repeat expansion of NOTCH2NLC. Despite the identification of uN2CpolyG, a toxic polyglycine (polyG) protein, the pathogenic mechanisms of NIID remain unclear. Herein, we investigated the role of polyG by expressing wild-type NOTCH2NLC, expanded NOTCH2NLC with 100 GGC repeats (translating or not translating into uN2CpolyG), or mutated NOTCH2NLC that encodes a pure polyG without GGC-repeat RNA and C-terminal stretch (uN2CpolyG-dCT) in mice. Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and caused neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathological lesions such as white matter lesions, microgliosis, and astrogliosis. By contrast, the sole expression of GGC-repeat RNA was non-pathogenic. Combining with bulk and single-nuclei RNA-seq, we determined the common molecular signatures associated with expressing uN2CpolyG and uN2CpolyG-dCT in the brain, especially the up-regulation of inflammation and microglia markers whereas down-regulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients by positron emission tomography, which correlated with white matter atrophy levels. Moreover, microglia ablation ameliorated neurodegeneration in uN2CpolyG-expressing mice but did not alter polyG inclusions. Together, these results demonstrate that polyG is critical for the pathogenesis of NIID, and microglia contribute to polyG-induced neurodegeneration.
2024-07-04 | GSE268950 | GEO
Project description:Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by GGC repeat expansion of NOTCH2NLC. Despite the identification of uN2CpolyG, a toxic polyglycine (polyG) protein, the pathogenic mechanisms of NIID remain unclear. Herein, we investigated the role of polyG by expressing wild-type NOTCH2NLC, expanded NOTCH2NLC with 100 GGC repeats (translating or not translating into uN2CpolyG), or mutated NOTCH2NLC that encodes a pure polyG without GGC-repeat RNA and C-terminal stretch (uN2CpolyG-dCT) in mice. Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and caused neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathological lesions such as white matter lesions, microgliosis, and astrogliosis. By contrast, the sole expression of GGC-repeat RNA was non-pathogenic. Combining with bulk and single-nuclei RNA-seq, we determined the common molecular signatures associated with expressing uN2CpolyG and uN2CpolyG-dCT in the brain, especially the up-regulation of inflammation and microglia markers whereas down-regulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients by positron emission tomography, which correlated with white matter atrophy levels. Moreover, microglia ablation ameliorated neurodegeneration in uN2CpolyG-expressing mice but did not alter polyG inclusions. Together, these results demonstrate that polyG is critical for the pathogenesis of NIID, and microglia contribute to polyG-induced neurodegeneration.
2024-07-04 | GSE269183 | GEO
Project description:GGC repeat expansion within NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here we have established both a transgenic mouse model and a human neural progenitor cell (hNPC) model. We show that the expression of the NOTCH2NLC gene with expanded GGC repeats produces multiple forms of polypeptides, including polyglycine (polyG), polyalanine (polyA) and polyarginine (polyR), and leads to widespread intranuclear inclusions, severe neurodegeneration, motor dysfunction and cognitive deficits, which faithfully mimics the clinical manifestations and pathological features associated with NIID. We further performed RNA-seq on the prefrontal cortex, cerebellum and hippocampus of the transgenic mice and on the hNPC model and identified a large proportion of conserved alternative splicing between the NIID mouse and hNPC cell models. Analyses of the conserved alternative splicing revealed the enrichment of the binding motif of hnRNPM. We found that hnRNPM could interact with and be sequestered by expanded NOTCH2NLC-polyG and -polyA. Functional expression of hnRNPM could ameliorate the cellular toxicity caused by expanded GGC repeats within NOTCH2NLC. These results together suggest that dysregulated alternative splicing could play a vital role in the molecular pathogenesis of NIID.
2023-01-04 | GSE182878 | GEO
Project description:3 to 6% of the human genome is composed of microsatellite sequences, which are short DNA elements composed of 2 to 6 nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as non-coding, thus questioning how they are pathogenic. Here, we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without leukoencephalopathy (OPDM/OPML) are located within previously unrecognized open reading frames (ORFs), resulting in their translation into novel polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet unrecognized small ORFs.
2026-02-03 | PXD071983 | Pride
Project description:Protein aggregates are a hallmark of neurodegenerative disease proposed to promote neurotoxicity through a diverse and growing set of mechanisms. Aggregation of polyglycine is specifically implicated in the pathogenesis of an emerging group of neurodegenerative GGC repeat expansion diseases. Here, we find that polyglycine aggregates incorporate endogenous proteins harboring glycine-rich sequences, including FAM98B, a conserved component of the vertebrate tRNA ligase complex. Through sequestration and accelerated proteosome-dependent turnover mediated by the FAM98B glycine-rich intrinsically disordered region (IDR), polyglycine depletes the ligase complex and disrupts tRNA processing.
2025-07-17 | GSE246377 | GEO
Project description:The protein interactome of polyG inclusions was investigated in HEK293T cells by isolating polyG inclusions followed by mass spectrometry. Briefly, HEK293T cells expressing polyG–EGFP were lysed, and polyG inclusions were enriched by differential centrifugation and subsequent high-salt washes. The purified inclusion fraction was then subjected to mass spectrometry for proteomic identification of associated proteins.
2026-01-20 | PXD072293 | Pride
Project description:Protein aggregates are a hallmark of neurodegenerative disease proposed to promote neurotoxicity through a diverse and growing set of mechanisms. Aggregation of polyglycine is specifically implicated in the pathogenesis of an emerging group of neurodegenerative GGC repeat expansion diseases. Here, we find that polyglycine aggregates incorporate endogenous proteins harboring glycine-rich sequences, including FAM98B, a conserved component of the vertebrate tRNA ligase complex. Through sequestration and accelerated proteosome-dependent turnover mediated by the FAM98B glycine-rich intrinsically disordered region (IDR), polyglycine depletes the ligase complex and disrupts tRNA processing. Accordingly, brains of affected patients reveal aggregate-associated sequestration and depletion of the tRNA-LC as well as accumulation of aberrant tRNA species.
2025-07-17 | GSE283760 | GEO
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2021-06-18 | GSE178466 | GEO
Project description:Arctigenin (ATG) is a major component of Fructus Arctii, which as a traditional herbal remedy reduced proteinuria in diabetic patients. However, whether ATG specifically provided renoprotection in DKD was not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via its interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results clearly demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.
2019-07-17 | GSE134327 | GEO